AU641286B2 - Process for the preparation of carebastine - Google Patents
Process for the preparation of carebastine Download PDFInfo
- Publication number
- AU641286B2 AU641286B2 AU86042/91A AU8604291A AU641286B2 AU 641286 B2 AU641286 B2 AU 641286B2 AU 86042/91 A AU86042/91 A AU 86042/91A AU 8604291 A AU8604291 A AU 8604291A AU 641286 B2 AU641286 B2 AU 641286B2
- Authority
- AU
- Australia
- Prior art keywords
- carebastine
- ebastine
- preparation
- cunninghamella
- microorganisms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- XGHOVGYJHWQGCC-UHFFFAOYSA-N carebastine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 XGHOVGYJHWQGCC-UHFFFAOYSA-N 0.000 title claims description 22
- 229950010123 carebastine Drugs 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 8
- 229960001971 ebastine Drugs 0.000 claims description 12
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 claims description 12
- 244000005700 microbiome Species 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 241000235555 Cunninghamella Species 0.000 claims description 2
- 241000233866 Fungi Species 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 241000235556 Cunninghamella elegans Species 0.000 description 7
- 241000010216 Cunninghamella blakesleeana Species 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SNDGLCYYBKJSOT-UHFFFAOYSA-N 1,1,3,3-tetrabutylurea Chemical compound CCCCN(CCCC)C(=O)N(CCCC)CCCC SNDGLCYYBKJSOT-UHFFFAOYSA-N 0.000 description 1
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 1
- -1 1-ethyl- Chemical group 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- ZWXPDGCFMMFNRW-UHFFFAOYSA-N N-methylcaprolactam Chemical compound CN1CCCCCC1=O ZWXPDGCFMMFNRW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000015244 frankfurter Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000000039 preparative column chromatography Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
Our Ref: 405152 )'41286 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT 0 0000 9
*B~
0 0 Applicant(s): Address for SerVice: Merck Patent Gesellschaft Mit Beschrankter Haftung Frankfurter Strasse 250 D-6100 DARMSTADT 1
GERMANY
ARTHUR S. CAVE CO.
Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Process for the preparation of carebastine Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 -1- Process for the preparation of carebastine The invention relates to a novel process for the preparation of carebastine, characterised in that ebastine is oxidised with a microorganism.
The chemical preparation of carebastine is disclosed in EP 134 124 but in this method an ester derivative is hydrolysed.
The object of the invention is to develop an improved process for the preparation of carebastine, which has pharmaceutical value.
Ebastine is 4.diphenylmethoxy-l-[3-(4-tert.butyl-benzoyl)-propyl]--piperidine. Its structure is: CH-O N SO
CH
3 ebastine Carebastine is 4-[4-(4-diphenylmethoxy)-l-piperidinyl)-l-oxobutyl]-phenyl-l,1dimethylacetic acid. Its structure is: CH-O N COOH carebastine
V..
*"It has been found that ebastine is, surprisingly, oxidised by microorganisms o selectively to carebastine. This novel process has the advantage by comparison with the 4 known process that it provides traightforward access to carebastine avoiding multistage chemical syntheses with far lower selectivity. In addition, the novel method can easily be transferred to industrial scales and therefore has the advantage by comparison with the A ,fp la conventional process that carebastine can be obtained therewith for the first time in relatively large amounts and in good overall yield, The process is also suitable for the oxidation of similar compounds, especially for the oxidation of terfenadine.
Carebastine can be used as active substance in pharmaceuticals in human and veterinary medicine, especially as antiallergic and for the treatment of cardiovascular disorders.
In detail, ebastine is expediently added directly or in solution, preferably in dimethylformamide (DMF), but also in dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethoxyethane (DME), tetrahydrofuran (THF) and dibutyl-, diisopropyl-, diethylformamide, 1-methyl-, 1-ethyl-, I-cyclohexylpyrrolidone, 4-formylmorpholine, 1-formylpiperidine, 1-formylpyrrolidine, tetramethyl-, tetraethyl-, tetrabutylurea, tripiperidino-, tripyrtolidino-phosphine oxide, sulfolane or N-methylcaprolactam or a 0* 0** so** 0
S
*0 r~ 2 mixtures of the said solvents, at a pH between 3 and 9, but especially in the neutral range, to a culture solution of the microorganisms, which is prepared by processes known per se, and incubated at a temperature between about 10 and 60"C, preferably 25-35"C, for 2-200 hours, preferably 1 week.
The invention furthermore relates to the use of microorganisms, preferably of filamentous fungi, preferably of the genus Cunninghamella, especially of the species Cunninghamella elegans, but also Cunninghamella blakesleeana, for the chemoselective oxidation of Sebastine.
Example 1 0.5 1 of culture solution (pH 7.0) is inoculated .15 with Cunninghamella elegans (DSM 1908). After culturing at 28 0 C for three days, 50 mg of ebastine dissolved in ml of DMF are added. After further incubation at 28 0
C
for 5 days, the resulting suspension is acidified with HC1 and extracted with dichloromethane. The organic phase is dried over sodium sulfate and then the solvent is removed. The carebastine obtained as residue is purified by preparative TLC or column chromatography (dichloromethane/methanol 10 1; silica gel); melting point 93- 0
C.
Example 2 Cunninghamella blakesleeana (ATCC 8688a) is S" cultivated in 1 1 of culture solution at a pH of 7. 0.5 g of ebastine dissolved in 5 ml of DMF is added to the culture. The incubation is carried out at 30 0 C for 1 week. Working up in analogy to Example 1 yields carebastine; melting point 93-95"C.
Example 3 0.2 g of ebastine dissolved in 2 ml of DMSO is added to 1 1 of culture solution of Cunninghamella elegans (DSM 1908) at pH 6. After incubation at 30"C for 4 days, working up is carried out in analogy to Example 1, and carebastine is obtained; melting point 93-95 0
C.
3 Example 4 The experiment is carried out in analogy to Example 1 in a 100 1 reactor by adding 5 g of ebastine dissolved in 50 ml of DMF to 100 1 of culture solution of Cunninghamella elegans (DSM 1908). Working up in analogy to Example 1 yields carebastine; melting point 93-95"C.
Example Cunninghamella blakesleeana (ATCC 8688a) is cultivated in 1 1 of culture solution for 3 days. The cells are thoroughly washed and separated from the nutrient medium, washed twice with phosphate buffer (0.1 M; pH 7.2) and resuspended in the same buffer. 0.1% ebastine is added to the cell suspension. After incubation at 28"C for 7 days, working up is carried out in *15 analogy to Example 1. Carebastine is obtained; melting point 93-95"C.
Example 6 Cunninghamella elegans (DSM 1908) is employed in place of Cunninghamella blakesleeana (ATCC 8688a) in analogy to Example 5. Culturing, incubating and working up in accordance with Example 5 yields carebastine; melting point 93-95°C.
to 4 6 .~a 042 Oe/SC 4- The microorganisms referred to in the claims have been deposited with the German Collection of Microorganisms and Cell Cultures (DSX) and are available in the public collection of the DSM. The deposit details are as follows:- Taxonomic Designation of Microorganism DSM Access No. Date of Depos it 24.9.80 30.9.80 Cunninghamella blakesleeana Cunninghamella elegans 1906 1908 .9 9 9*
S.
*9tt **99 9 9* 9 9 5 *064 a.
5 9 S V St 5* 5* *5 9 5S *9 9 9SSb 6 4 9* 9 9955 The corresponding ATCC accession numbers are as follows: Cunninghamella blakesleeana Cunninghamella elegans (DSM 1906) (DSM 1908) ATCC 8688a ATCC 9245
Claims (4)
1. Process for the preparation of carebastine, characterised in that ebastine is oxidised by a microorganism to produce carebastine.
2. Use of microorganisms for the chemoselective oxidation of ebastine to carebastine.
3. The process of claim 1 wherein the microorganisms are filamentous fungi of the species Cunninghamella.
4. A process for the preparation of carebastine substantially as herein described with reference to any one of the examples. DATED this 6th day of July 1993. MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG By their Patent Attorneys DAVIES COLLISON CAVE p^ S 4 4**a Oe 4 4 4 4 4444
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4034218A DE4034218A1 (en) | 1990-10-27 | 1990-10-27 | METHOD FOR PRODUCING CAREBASTIN |
| DE4034218 | 1990-10-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8604291A AU8604291A (en) | 1992-04-30 |
| AU641286B2 true AU641286B2 (en) | 1993-09-16 |
Family
ID=6417164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU86042/91A Ceased AU641286B2 (en) | 1990-10-27 | 1991-10-21 | Process for the preparation of carebastine |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5204249A (en) |
| EP (1) | EP0483597A3 (en) |
| JP (1) | JPH0515386A (en) |
| KR (1) | KR920008193A (en) |
| AU (1) | AU641286B2 (en) |
| CA (1) | CA2054239A1 (en) |
| CS (1) | CS324791A3 (en) |
| DE (1) | DE4034218A1 (en) |
| HU (1) | HU208554B (en) |
| IE (1) | IE913749A1 (en) |
| PT (1) | PT99341A (en) |
| TW (1) | TW222675B (en) |
| ZA (1) | ZA918534B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1178041A1 (en) * | 1994-05-18 | 2002-02-06 | Aventis Pharmaceuticals Inc. | Process for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives |
| US20030045722A1 (en) * | 1994-05-18 | 2003-03-06 | Henton Daniel R. | Processes for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof |
| US6201124B1 (en) * | 1995-12-21 | 2001-03-13 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
| US6153754A (en) * | 1995-12-21 | 2000-11-28 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
| EP0864653B1 (en) * | 1997-03-11 | 2004-03-03 | Aventis Pharmaceuticals Inc. | Process for production of 4-(4-(4-(hydroxydiphenyl)-1-piperidinyl)-1-hydroxybutyl)-alpha, alpha-dimethylphenyl acetic acid and phosphorylated derivatives |
| DE19709898A1 (en) * | 1997-03-11 | 1998-09-24 | Hoechst Marion Roussel De Gmbh | Preparation of new and known piperidine derivatives comprises incubating Cunninghamella or Absidia fungus |
| US6613907B2 (en) | 2000-11-08 | 2003-09-02 | Amr Technology, Inc. | Process for the production of piperidine derivatives with microorganisms |
| TW200517114A (en) | 2003-10-15 | 2005-06-01 | Combinatorx Inc | Methods and reagents for the treatment of immunoinflammatory disorders |
| ES2335608T3 (en) * | 2005-06-09 | 2010-03-30 | Elan Pharma International Limited | NANOPARTICULATED EBISTINE FORMULATIONS. |
| JP2009514969A (en) | 2005-11-09 | 2009-04-09 | コンビナトアールエックス インコーポレーティッド | Methods, compositions, and kits for treating medical conditions |
| US20100092479A1 (en) * | 2008-08-18 | 2010-04-15 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
| US20110130711A1 (en) * | 2009-11-19 | 2011-06-02 | Follica, Inc. | Hair growth treatment |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3822188A (en) * | 1972-10-19 | 1974-07-02 | Abbott Lab | Method of producing 1,4'-dihydroxy-3-n-pentyl-6,6,9-trimethyl-6a,7,10,10a-tetra-hydrodibenzo(b,d)pyran |
| US4064009A (en) * | 1976-06-09 | 1977-12-20 | Eli Lilly And Company | Novel 3-(oxygenated alkyl)-1,9-dihydroxy and 1-hydroxy-9-keto dibenzo[b,d]py |
| US4153509A (en) * | 1977-10-17 | 1979-05-08 | Union Carbide Corporation | Microbial production of hydroxylated biphenyl compounds |
| GB8321157D0 (en) * | 1983-08-05 | 1983-09-07 | Fordonal Sa | Piperidine derivatives |
| FR2585366B1 (en) * | 1985-07-23 | 1987-09-11 | Nativelle Sa Ets | PROCESS FOR THE MICROBIOLOGICAL HYDROXYLATION OF QUININE, QUINIDINE, AND DERIVATIVES |
-
1990
- 1990-10-27 DE DE4034218A patent/DE4034218A1/en not_active Withdrawn
-
1991
- 1991-10-16 EP EP19910117619 patent/EP0483597A3/en not_active Withdrawn
- 1991-10-21 AU AU86042/91A patent/AU641286B2/en not_active Ceased
- 1991-10-24 JP JP3303784A patent/JPH0515386A/en active Pending
- 1991-10-24 TW TW080108409A patent/TW222675B/zh active
- 1991-10-25 CA CA002054239A patent/CA2054239A1/en not_active Abandoned
- 1991-10-25 PT PT99341A patent/PT99341A/en not_active Application Discontinuation
- 1991-10-25 US US07/783,024 patent/US5204249A/en not_active Expired - Fee Related
- 1991-10-25 HU HU913366A patent/HU208554B/en not_active IP Right Cessation
- 1991-10-25 IE IE374991A patent/IE913749A1/en not_active Application Discontinuation
- 1991-10-25 CS CS913247A patent/CS324791A3/en unknown
- 1991-10-25 ZA ZA918534A patent/ZA918534B/en unknown
- 1991-10-26 KR KR1019910018926A patent/KR920008193A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| US5204249A (en) | 1993-04-20 |
| EP0483597A2 (en) | 1992-05-06 |
| HU208554B (en) | 1993-11-29 |
| CS324791A3 (en) | 1992-05-13 |
| JPH0515386A (en) | 1993-01-26 |
| IE913749A1 (en) | 1992-05-22 |
| HUT62941A (en) | 1993-06-28 |
| KR920008193A (en) | 1992-05-27 |
| ZA918534B (en) | 1992-08-26 |
| AU8604291A (en) | 1992-04-30 |
| TW222675B (en) | 1994-04-21 |
| DE4034218A1 (en) | 1992-04-30 |
| CA2054239A1 (en) | 1992-04-28 |
| EP0483597A3 (en) | 1992-05-20 |
| PT99341A (en) | 1992-09-30 |
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